Genetic Variant NM_002516.4:c.1087A>T (chr19-45940255-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002516.4(NOVA2):c.1087A>T(p.Asn363Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000683 in 146,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOVA2
NM_002516.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

Publications

0 publications found

Variant links:

Genes affected

NOVA2 (HGNC:7887): (NOVA alternative splicing regulator 2) Enables sequence-specific mRNA binding activity. Involved in neuron differentiation and regulation of alternative mRNA splicing, via spliceosome. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NOVA2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

NOVA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3894005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOVA2	NM_002516.4	MANE Select	c.1087A>T	p.Asn363Tyr	missense	Exon 4 of 4	NP_002507.1	Q9UNW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOVA2	ENST00000263257.6	TSL:1 MANE Select	c.1087A>T	p.Asn363Tyr	missense	Exon 4 of 4	ENSP00000263257.4	Q9UNW9
	NOVA2	ENST00000676183.1		c.1279A>T	p.Asn427Tyr	missense	Exon 4 of 4	ENSP00000501708.1	A0A6Q8PFC2

Frequencies

GnomAD3 genomes

AF:

0.00000683

AC:

AN:

146390

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

942978

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

444880

African (AFR)

AF:

0.00

AC:

AN:

18078

American (AMR)

AF:

0.00

AC:

AN:

4120

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8118

East Asian (EAS)

AF:

0.00

AC:

AN:

11048

South Asian (SAS)

AF:

0.00

AC:

AN:

18486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2150

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

835270

Other (OTH)

AF:

0.00

AC:

AN:

33788

GnomAD4 genome

AF:

0.00000683

AC:

AN:

146390

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40630

American (AMR)

AF:

0.00

AC:

AN:

14692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3404

East Asian (EAS)

AF:

0.00

AC:

AN:

4838

South Asian (SAS)

AF:

0.00

AC:

AN:

4472

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8958

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66142

Other (OTH)

AF:

0.00

AC:

AN:

2034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

PhyloP100

5.4

PrimateAI

Pathogenic

0.98

PROVEAN

Benign

-1.1

REVEL

Benign

0.22

Sift

Uncertain

0.0030

Sift4G

Benign

0.36

Polyphen

1.0

Vest4

0.45

MutPred

0.35

Gain of helix (P = 0.0496)

MVP

0.47

ClinPred

0.82

GERP RS

3.6

Varity_R

0.12

gMVP

0.42

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over